Do we need to continue androgen deprivation therapy?

There is an on-going discussion on the value and need of androgen deprivation therapy (ADT) in this highly palliative stage of the disease. Should ADT be continued when abiraterone, enzalutamide, or chemotherapy are initiated? Are there downsides to ADT in this stage? Does it affect the health-related quality of life (HRQoL)? Those questions are worthy of scrutiny.

This article is based on today’s presentation which will focus on the evidence for maintaining ADT in CRPC patients, the statements provide basis for a discussion of the evidence and the rationale behind the recommendation if/that ADT should be continued in mCRPC.

The European Association of Urology (EAU) guideline clearly states that patients with metastatic castrateresistant prostate cancer (mCRPC) should indefinitely continue androgen deprivation therapy (ADT); this recommendation applies to metastatic CRPC (mCRPC) and non-metastatic CRPC (nmCRPC)¹. Other guidelines, such as that from the American Urological Association (AUA)² and the National Comprehensive Cancer Network (NCCN)³, likewise mention the need to maintain ADT when mCRPC develops.

As support, all randomised controlled trials of the many newer agents for mCRPC, including abiraterone, enzalutamide, sipuleucel-T, radium 223 and cabazitaxel^4-10 all had continuation of ADT and mainstay of castration levels of testosterone (<50 ng/ dl) as an inclusion criterion. However, this does not prove the value of ADT in this setting. In metastatic disease, while hormonal treatment improves symptoms¹¹, there is no conclusive prospective evidence that lowering testosterone levels improves life expectancy¹². With the event of evaluating novel substances in the setting of non-metastatic CRPC, the value of combining ADT with tertiary hormonal manipulation (e.g. Enzalutamide, Abiraterone, ARN-509, etc.) has not been investigated.

Sparse evidence

The evidence for continuing ADT in metastatic prostate cancer is based on sparse literature. A single study demonstrated that androgen priming in a small group of patients (n=85) using chemotherapy regimens that are now outdated altered the prognosis¹³.

However, it is becoming clear that within the prostate and prostate tumour microenvironment androgen activity continues even when serum testosterone levels are suppressed by ADT¹⁴, and intracrine androgen synthesis is sufficient to activate androgen receptor target genes¹⁵. Adaptive alterations include alternative androgen synthesis pathways, and androgen receptor overexpression, mutation and splice variations¹⁶. Furthermore, many mechanisms that may confer castration-resistance still require, or are enhanced by, the presence of androgens or androgen receptor ligands. Together these observations suggest that treatment combinations that include ADT and suppress intracrine and systemic androgen contributions are required in CRPC.

The presentation will cover the evidence and rationale for continuing ADT in CRPC when other treatments are initiated, and aim to provide clear statements on this issue.

The rationale for ADT use in combination with abiraterone acetat

Abiraterone acetat selectively inhibits the enzyme 17 α-hydroxylase/C17, 20-lyase (CYP17) and thus inhibits androgen biosynthesis¹⁸. Abiraterone acetat also has direct activity on reducing the expression of the androgen receptor gene in tumour cells¹⁹. This underscores the need to target as many parts of the androgen receptor signalling pathway as possible and therefore providing a rationale for combining abiraterone with ADT. Remarkably, experimental evidence suggests that the testosterone suppression achieved by abiraterone monotherapy is not sustained in non-castrated men and is overcome by a subsequent two- to three-fold surge in luteinising hormone (LH) levels²⁰. Although the pharmacokinetic study of O’Donnell et al²⁰ assessed a small number of men, it does suggest a need to maintain castrate levels of testosterone with ADT when initiating abiraterone therapy.

This rationale has been used in the pivotal phase III trials of abiraterone. The efficacy of abiraterone in combination with prednisolone was demonstrated in two trials in patients with mCRPC as previously published^4,5 (LoE: 1b). Importantly, castration levels of testosterone were maintained in both these studies with the continuation of ADT.

Currently, a German multicentre trial (SPARE trial) is investigating the impact of continuing ADT when initiating abiraterone. This study (German Association of Urological Oncology trial number AUO 67/11) is investigating abiraterone monotherapy (plus prednisolone) versus abiraterone plus ADT (plus prednisolone) in 70 men with chemotherapy-naïve mCRPC. Preliminary results of this study should be available in 2016, which will provide the first prospective insight on the potential efficacy advantages of maintaining ADT when abiraterone treatment is initiated in mCRPC. Interestingly, there is no published data assessing abiraterone (with or without ADT) in patients with non-metastatic CRPC (nmCRPC). More data on the use of newer agents for the treatment of nmCRPC are needed.

The rationale for ADT use with enzalutamide

Androgen receptor signalling persists during castration, and several mechanisms, even in individual patients (through clonal heterogeneity), may explain this persistence²³. Addition of androgen receptor blockers to ADT may therefore help achieve more complete androgen blockade. With the development of the novel androgen receptor blocker enzalutamide, which binds to the androgen receptor with eight-fold higher affinity than bicalutamide³², it is important to ask whether there is any clinical need to combine enzalutamide treatment with ADT.

To date, however, there have been no clinical trials comparing enzalutamide monotherapy with enzalutamide plus ADT to confirm the need for continued ADT when initiating abiraterone therapy in patients with mCRPC. Unlike bicalutamide, enzalutamide has no known agonist activity, and it is thought that bicalutamide resistance does not exclude subsequent enzalutamide use³². In addition, a recent report has assessed enzalutamide monotherapy in hormone-naive men with prostate cancer³³. This initial report of enzalutamide monotherapy in 67 patients suggested a lower frequency of gynaecomastia (36%) than previously reported with bicalutamide monotherapy. Furthermore, PSA declines were of a similar magnitude to those achieved by ADT but adverse events were frequent and testosterone levels increased³³.

Therefore, more data are needed to determine whether the combination of enzalutamide with ADT has a favourable efficacy and safety profile for the treatment of CRPC compared with enzalutamide monotherapy. In the meantime, as with abiraterone, pivotal trials of enzalutamide in men with CRPC included the need for castration maintenance with ADT6,7; these studies have shown that this combination improved OS when used before chemotherapy and after chemotherapy.

Ongoing clinical studies may provide some clues to the need for backbone ADT when initiating enzalutamide in patients with CRPC. However, there are no trials with enzalutamide that are equivalent to the SPARE study with abiraterone, which directly compare enzalutamide monotherapy with enzalutamide combined with ADT in men with CRPC.

ADT during chemotherapy

EAU guidelines state that ADT with GnRH analogues should be continued when giving mCRPC patients chemotherapy1. The theory for continuing ADT when starting chemotherapy in mCRPC is that pausing ADT may lead to renewed release of testosterone and stimulation of the remaining androgen-sensitive elements of the tumour. Conversely, approximately 50% of men receiving ADT in the long-term remain castrated for 2.5 years after stopping ADT³⁴, and stopping ADT might re-induce hormone sensitivity³⁵.

These conflicting viewpoints are difficult to prove as there is a lack of well-designed prospective trials exploring this issue, and retrospective data are conflicting^36-38. There is no evidence that the combination of ADT with chemotherapy causes harm; however, there is also no strong evidence of benefit in this clinical scenario. Two ongoing studies (ClinicalTrials.gov identifiers: NCT01487902 and NCT01224405) are investigating the possible advantage of maintaining ADT during chemotherapy. One of these studies (NCT01487902) that is comparing docetaxel plus prednisolone with docetaxel plus prednisolone and leuprolide in approximately 90 men with CRPC was due for completion in October 2013, and results may therefore be available soon. Until these results are available ADT should be continued when chemotherapy is initiated in mCRPC in daily practice also according to the current guidelines.

Prospective data and biomarkers needed

All clinical trials of newer agents (and recent trials of chemotherapy agents) in mCRPC include patients who maintain castrate levels of testosterone, and so clinical practice should adhere to this principle of continuing ADT when initiating abiraterone, enzalutamide or chemotherapy. However, not only are more prospective data needed to assess the importance of backbone ADT in CRPC, but also reliable prognostic and predictive biomarkers are urgently needed to individualise treatment with newer agents, their combination with ADT, and the optimum treatment sequences.

References

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2. Cookson MS, Roth BJ, Dahm P, Engstrom C, Freedland SJ, Hussain M, et al. Castration-resistant prostate cancer: AUA guideline. 2013.

3. NCCN. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. 2014.

4. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983-92.

5. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48.

6. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187- 97.

7. Beer TM, Armstrong AJ, Sternberg CN, Higano CS, Iversen P, Loriot Y, et al. Enzalutamide in men with chemotherapy-naïve metastatic prostate cancer (mCRPC): results of phase III PREVAIL Study. J Clin Oncol. 2014;32 (suppl. 4):LBA1^.

8. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.

9. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-23.

10. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54.

11. Morote J, Orsola A, Planas J, Trilla E, Raventos CX, Cecchini L, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178:1290-5.

12. Merseburger AS, Hammerer P, Rozet F, Roumeguère T, Caffo O, da Silva FC, Alcaraz A. Androgen deprivation therapy in castrate-resistant prostate cancer: how important is GnRH agonist backbone therapy? World J Urol. 2014; Sept 27.

13. Manni A, Bartholomew M, Caplan R, Boucher A, Santen R, Lipton A, et al. Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome. J Clin Oncol. 1988;6:1456-66.

14. Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, et al. Intraprostatic androgens and androgenregulated gene expression persist after testosterone suppression: therapeutic implications for castrationresistant prostate cancer. Cancer Res. 2007;67:5033-41.

15. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-54.

16. Egan A, Dong Y, Zhang H, Qi Y, Balk SP, Sartor O. Castration-resistant prostate cancer: Adaptive responses in the androgen axis. Cancer Treat Rev. 2014;40:426-33.